Pharmaceutical composition

ABSTRACT

Particulate nedocromil sodium with a mass median diameter of from 5 to 10 μm is useful as a medicament for inhalation. 
     The particulate nedocromil sodium of the invention is particularly advantageous in that its dispersion, i.e. the proportion of particles which are capable of penetrating deep into the lung, is substantially greater than the dispersion of conventional powders having smaller mass median diameters.

This is a division of application Ser. No. 07/835,014, filed Feb. 12,1992 now U.S. Pat. No. 5,198,221 which is in turn a Continuation of Ser.No. 07/522,998, filed on May 14, 1990, now abandoned.

This invention relates to a novel powder form of the known medicamentnedocromil sodium, and to pharmaceutical formulations comprising thatpowder form.

Nedocromil sodium, the disodium salt of9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylic acid, is known, for example from BritishPatent Application No 2157291, to be of use in the treatment ofreversible obstructive airways disease when administered to the lung infinely divided solid form.

An important parameter affecting the efficacy of powder formulations forinhalation is the `dispersion` i.e. the proportion of the inhaled powdercloud which is fine enough to penetrate deep into the lung. Foradministration in this form, it has previously generally been consideredthat the dispersion of inhalation medicaments improves as the averageparticle size is reduced. European Patent No 0072046, for example,states that the smaller the mass median diameter, the higher will be thedispersion. The above mentioned British Patent Application No 2157291 isconsistent with this, since it expresses a preference for nedocromilsodium with a mass median diameter of less than 4 μm, and particularlyless than 3 μm.

We have now surprisingly found that nedocromil sodium powders withaverage particle sizes considerably greater than those previouslyconsidered desirable actually give better dispersion than such finerpowders.

According to the invention there is provided particulate nedocromilsodium with a mass median diameter of from 5 to 10 μm.

The particulate nedocromil sodium of the invention is advantageous inthat its dispersion, i.e. the proportion of particles which are capableof penetrating deep into the lung, is substantially greater than thedispersion of conventional powders having smaller mass median diameters.This increases the effective dose administered and may enable the use oflower total dosages. In addition, the material may exhibit otheradvantageous properties, e.g. improved emptying from the device used foradministration and/or greater efficacy when administered at low ormoderate flow rates.

The mass median diameter, as is known by those skilled in the art, isdefined such that 50% by mass of the particulate material is in the formof particles having a smaller diameter. Throughout this specification,the term is used to indicate the mass median diameter as determined bylaser diffraction light scattering techniques. Similarly, other particlesizes referred to are as measured by these techniques. The use of othermethods of particle sizing may give results which differ somewhat fromthose obtained by the light scattering technique.

We prefer the mass median diameter of the particulate nedocromil sodiumaccording to the invention to be less than 9 μm.

Thus, we prefer the mass median diameter of the particulate nedocromilsodium according to the invention to be in the range 5 to 9 μm.

The particle size distribution of the particulate nedocromil sodium mayalso be characterised in terms of the mass fractions above or belowcertain limits. We prefer the mass fraction of material which is presentas particles with a diameter greater than 10 μm to be less than 40%. Themass fraction of the medicament which is present as particles which havea diameter of less than 3 μm is preferably more than 5%, and morepreferably more than 10%.

The particle size distribution may also be characterised by thegeometric standard deviation SD_(geo). This quantity may be obtainedfrom a logarithmic plot of the cumulative percentage less than a statedsize against the logarithm of the size. Such a plot is generally astraight line and SD_(geo) can be obtained from the relation ##EQU1##(see Eugene L Parrott in The Theory and Practice of Industrial Pharmacy,Chapter 2, page 21, published by Lea & Febiger, Philadelphia) in which`n % size` is the diameter for which n % of the material is smaller thanthe stated size. In this specification, geometric standard deviationsare quoted on a mass basis, though in practice geometric standarddeviations for weight and number distributions are practicallyidentical.

We prefer the geometric standard deviation of the particle sizedistribution to be in the range 1.5 to 3.0, more preferably 2.0 to 2.7.

According to a particularly preferred aspect of the invention there isprovided particulate nedocromil sodium having a mass median diameter offrom 5 to 10 μm and a geometric standard deviation of from 1.5 to 3.0.

As mentioned above, particle sizes quoted in this specification are asdetermined by laser diffraction light scattering techniques. Othersuitable methods of particle size determination may be used. In general,such methods will be well known to those skilled in the art and includemicroscopy and sedimentation. Sieving methods, which are also widelyused for particle size determination, are generally not suitable in thepresent case due to the small size of the particles. More details ofmethods of particle size determination may be obtained from, forexample, the article by Parrott referred to above and the referencestherein.

The particulate nedocromil sodium according to the invention may beprepared by conventional methods used for the preparation of finelydivided material, e.g. milling and micronisation. Various types of millmay be used but we have found the use of a hammer mill to beparticularly convenient. The hammer mill is well known and is an impactmill using a high speed rotor to which a number of swinging hammers arefixed. The material is fed at the top or centre, thrown outcentrifugally, and ground by impact of the hammers or against platesaround the periphery of the casting. The clearance between the housingand the hammers contributes to the size reduction. The material isretained until it is small enough to fall through the screen that formsthe lower portion of the casing. Particles fine enough to pass throughthe screen are discharged almost as fast as they are formed.

The optimum operating conditions for the hammer mill will vary dependinginter alia on the particle size of the material fed to the mill, theparticular model of mill used etc. Parameters which may be variedinclude the rotational speed of the rotor and the form (thickness andmesh size) of screen employed.

The use of a hammer mill is preferred because it is particularlysuitable for the production of material with the appropriate particlesize and is generally simple to install and operate. The rotationalspeed and screen can be rapidly changed and particulate material with arelatively narrow particle size distribution is obtained.

The particulate nedocromil sodium according to the invention willgenerally be manufactured in a form suitable for direct administrationto a patient. For example, the material may be formulated as the activeingredient in a composition containing the particulate nedocromil sodiumin admixture with a solid pharmaceutically acceptable carrier having aneffective particle size of from 30 to 120 μm.

The term `effective particle size` is used to denote the apparentparticle size of a body without distinction as to the number ofindividual particles which go to make up that body i.e. no distinctionis made between a single particle of given size and an agglomerate ofthe same size which is composed of finer individual particles.

The solid pharmaceutically acceptable carrier in the composition willgenerally be a non-toxic material chemically inert to nedocromil sodiumbut may, if so desired, also comprise larger particles of nedocromilsodium. Examples of carriers which may be used in the compositioninclude a dextran, mannitol and, preferably, lactose. A particularlypreferred carrier is crystalline lactose.

The particles of carrier preferably have a mass median diameter of fromabout 30 to 150 μm. The mass median diameter is preferably less than 100μm and more preferably less than 80 μm. It is particularly preferredthat the mass median diameter of the carrier particles be in the range30 to 80 μm, e.g. about 50 to 60 μm.

According to a further, preferred aspect of the invention there isprovided a pharmaceutical composition comprising particles of nedocromilsodium having a mass median diameter of from 5 to 10 μm, in admixturewith a solid pharmaceutically acceptable carrier having a mass mediandiameter of from 30 to 80 μm, the proportion by weight of nedocromilsodium to carrier being in the range 1:4 to 4:1.

The particulate carrier may be prepared by grinding the carrier andsubsequently separating out the desired fraction by conventionalmethods, e.g. by air classification and sieving.

The composition may be prepared by mixing the ingredients together in amixer, e.g. a planetary or other stirred mixer. The invention thus alsoprovides a method for preparing a composition of the invention whichcomprises mixing together particulate nedocromil sodium according to theinvention and the coarse carrier, after comminution and particle sizeclassification of the ingredients if this is necessary.

The particulate nedocromil sodium may also be formulated as a so-called`pelletised` composition, i.e. as soft pellets of diameter greater than30 μm, each pellet comprising a plurality of individual particlesloosely held together such that upon inhalation the pellets disintegrateto the constituent particles.

The compositions according to the invention may be put up in gelatine,plastics or other capsules.

The amount of composition contained in the capsule will, of course, tosome extent depend on the desired dosage, but will generally be fromabout 10 to 50 μmg, e.g. 20 mg. The proportion of nedocromil sodium inthe composition will typically be from about 25 to 50%.

There is also provided therefore, as a further feature of the invention,a dosage unit comprising a capsule containing from 10 to 50 mg of apharmaceutical composition comprising particles of nedocromil sodiumhaving a mass median diameter of from 5 to 10 μm in admixture withcoarser particles of a solid pharmaceutically acceptable carrier.

A method of preparation of nedocromil sodium is described in CanadianPatent No 1112644. A form of nedocromil sodium which is particularlywell suited to grinding and a method of preparing such that form isdescribed in British Patent Application No 2157291.

The present invention will now be illustrated by the following Examples.

EXAMPLE 1 Preparation of Nedocromil Sodium according to the Invention

Recrystallised nedocromil sodium, prepared by a method similar to thatof Example 2 of British Patent Application No 2157291, was passedthrough a hammer mill (Model TBEP manufactured by Apex Construction Ltd,Dartford, UK) operating at a rotational speed of 3450 rpm with a screensize of 2 mm and the milled product collected in kegs with doublepolyethylene lining.

EXAMPLE 2 Particle size determination

The particle size distribution of milled nedocromil sodium prepared asdescribed in Example 1 was determined using a Malvern 2600 Series LaserDiffraction Particle Sizer (Malvern Instruments plc, Malvern, UK) fittedwith a 63 mm lens and operating in p-i-l (particles in liquid) mode, asfollows:

With the sample cell filled with filtered propan-2-ol, the optics werealigned and the diffracted light measured with no sample present toestablish the baseline. A small test tube was rinsed with propan-2-ol,then half filled with filtered propan-2-ol and a small sample of theparticulate nedocromil sodium was added. The tube was manually agitatedto facilitate wetting and placed in an ultrasonic bath for two minutesto disperse the solid particles.

Suspended particles from the testtube were added to the sample cell fromthe test tube using a Pasteur pipette untile the optimum sampleconcentration was reached, whereupon the measurement was made.

EXAMPLE 3 Comparison of Capsule Emptying and Dispersion for TwoFormulations of Nedocromil Sodium Method

Number 2 hard gelatine capsules were filled with 20 mg of 1:1 nedocromilsodium: lactose blends in which the nedocromil sodium had a mass mediandiameter (MMD) of approximately 2 μm and 8 μm.

The capsules were loaded into the inhaler sold under the registeredtrademark SPINHALER (Fisons plc). The device was discharged in amulti-stage impinger (described in, for example, Bell J. H., Hartley P.S., & Cox P. S. G., J Pharm Sci 60, 10 (1971)) at a flow rate of 60l/min or 120 l/min and the quantity of material retained in the deviceand the quantity of respirable material (particles of diameter less than7.5 μm at 60 l/min and 5.0 μm at 120 l/min) were measured.

Results

    ______________________________________                                                  quantity of nedocromil sodium/mg                                    Flow Rate   60 l/min        120 l/min                                         MMD (μm  2       8          2     8                                        ______________________________________                                        Device      3.75    2.40       4.56  2.11                                     retention                                                                     Fine particle                                                                             0.46    1.86       2.66  3.99                                     dose                                                                          ______________________________________                                    

EXAMPLE 4 Pharmaceutical Compositions Containing Nedocromil Sodium

    ______________________________________                                                         % w/w                                                        ______________________________________                                        a)       Nedocromil sodium                                                                           50                                                              Crystalline lactose                                                                         50                                                     b)       Nedocromil sodium                                                                           37.5                                                            Crystalline lactose                                                                         62.5                                                   c)       Nedocromil sodium                                                                           25                                                              Crystalline lactose                                                                         75                                                     ______________________________________                                    

In each case the nedocromil sodium has a mass median diameter ofapproximately 8 μm. The crystalline lactose is classified and has a massmedian diameter of approximately 55 μm. The compositions are prepared bymixing the ingredients in a planetary mixer.

We claim:
 1. A pharmaceutical inhalation composition comprising softpellets of nedocromil sodium of diameter greater than 30 μm, each pelletcomprising a plurality of individual particles loosely held togethersuch that upon inhalation the pellets disintegrate to the constituentparticles, the mass median diameter of the constituent particles beingfrom 5 to 10 μm with a particle size geometric standard deviation offrom 1.5 to 3.0.
 2. A pharmaceutical composition according to claim 1,wherein the mass median diameter of the constituent particles is lessthan 9 μm.
 3. A pharmaceutical composition according to claim 1, whereinthe mass fraction of material which is present as constituent particleswith a diameter greater than 10 μm is less than 40%.
 4. A pharmaceuticalcomposition according to claim 1, wherein the mass fraction of materialwhich is present as constituent particles which have a diameter of lessthan 3 μm is more than 5%.
 5. A pharmaceutical composition according toclaim 1, wherein the mass fraction of material which is present asconstituent particles which have a diameter of less than 3 μm is morethan 10%.
 6. A pharmaceutical composition according to claim 1, whereinthe geometric standard deviation of the particle size distribution isfrom 2.0 to 2.7.
 7. A capsule containing from 10 to 50 mg of apharmaceutical composition according to claim
 1. 8. A method oftreatment of reversible obstructive airways disease, which methodcomprises administration to a patient suffering from or susceptible tosuch a condition of a therapeutically effective quantity of apharmaceutical composition according to claim 1.